1. Field of the Invention
The chemical processes of the present invention produce novel antibacterial agents of the .beta.-lactam type containing a hitherto unknown nucleus and useful intermediates for their synthesis.
2. Description of the Prior Art
Penicillins and cephalosporins comprise a group of well-known antibacterial agents commonly grouped together as a class called .beta.-lactam antibiotics. For a recent review of this field with many citations (especially the first ten) to the prior work, see J. P. Hou and J. W. Poole, .beta.-lactam Antibiotics: Their Physiocochemical Properties and Biological Activities in Relation to Structure, J. Pharmaceutical Sciences, 60(4), 503-532 (Apr. 1971). Most of the work in this field has fundamentally been done, speaking broadly, with 6-aminopenicillanic acid, 7-aminocephalosporanic acid and derivatives thereof produced by fermentation or chemical transformation of the natural products. Despite the extensive progress made in preparing active derivatives of 6-aminopenicillanic acid and 7-aminocephalosporanic acid, there is a continuing search for synthetic and semi-synthetic routes to new families of .beta.-lactam antibiotics which may possess more advantageous properties then those derived from the known penicillin and cephalosporin nuclei.
Considerable work has been done on total chemical synthesis of both known .beta.-lactams and nuclear analogs of such known compounds. A recent review is the text by M. S. Manhas and A. K. Bose, Synthesis of Penicillin, Cephalosporin C and Analogues, Marcel Decker, Inc., 95 Madison Avenue, New York, New York, 1969. Another extensive review is by R. B. Morin and B. G. Jackson, Chemistry of Cephalosporin Antibiotics, Fortschr. Chem. Org. Naturst., 28, 343-403 (1970), especially pages 379-393; the now famous "Woodward Intermediate" is shown therein as compound 146 on page 387. A more recent review of .beta.-lactams is that by M. S. Manhas and A. K. Bose, Beta-Lactams: Natural and Synthetic: Part 1, Wiley-Interscience, New York, New York, 1971. A still further review article on the synthesis of .beta.-lactams is that by A. K. Mukerjee et al., Synthesis, 327 (1973).
Other pertinent publications relating to synthesis of .beta.-lactams are:
a. D. M. Brunwin, G. Lowe and J. Parker, J.C.S. Chem. Comm., 1971, 865-867, describing synthesis of nuclear analogs of the penicillin-cephalosporin group. PA1 b. D. M. Brunwin et al., J. Chem. Soc. (C), 1971, 3756-3762 and J.C.S. Chem. Comm., 1972, 589-590 describing total synthesis of nuclear analogs of penicillins and cephalosporins. PA1 c. S. Kukolja, J. Amer. Chem. Soc., 93, 6267-6270 (1971) and 94, 7590-7593 (1972) describing preparation of 6-phthalimido-5-epipenicillanates and disulfide analogs of penicillins. PA1 d. J. A. Webber et al., J. Medicinal Chemistry, 14(11), 1136-1138 (1971) describing preparation of 3-cyanomethyl cephem nucleus. PA1 e. West German Patent Specification No. 2,219,601 (Farmdoc 76,051T) describing synthesis of .beta.-lactams of the formula ##STR2## wherein X is halo, N.sub.3 -- or H.sub.2 N--, A is --S--, --S--CH.sub.2 --, --O--, --O--CH.sub.2 --, --CH.sub.2, --CH.sub.2 CH.sub.2 -- or --NH-- and R.sup.1, R.sup.2 and R.sup.3 are hydrogen, C.sub.1 -C.sub.6 alkyl or aryl. PA1 f. U.K. Pat. No. 1,308,822 disclosing .beta.-lactams of the formula ##STR3## where Y = amino or substituted amino. g. S. Wolfe et al., Can. J. Chem., 50, 2894-2905 (1972) describing synthesis of sulfur-free penicillin derivatives. PA1 h. French Patent 2,111,859 describing nuclei of the formula ##STR4## and 7-acylated derivatives thereof. i. Helvetica Chimica Acta, 55(2), 388-429 (1972) describing nuclear modified cephalosporins and penicillins. PA1 j. F. Moll et al., Zeit. fur Naturforsch. B, 27(b)6, 727 (1972) describing nuclear analogs of cephalosporins. PA1 k. U.K. Specifications 1,271,013 and 1,271,014 describing .gamma.-lactams of 7-(acylamino)-3-aminomethyl-ceph-3-em-4-carboxylic acids. PA1 l. U.K. Pat. Specification No. 1,271,180 describing preparation of novel thiazoline azetidinone rearrangement products useful as intermediates in penicillin and cephalosporin synthesis. PA1 m. German Patent Specifications Nos. 2,046,822, 2,046,823 and 2,046,824 describing synthesis of novel azetidinone intermediates. PA1 n. G. Lowe et al., J. Chem. Soc. Perkins I, 1322 (1973) describing total synthesis of nuclear analogs of 7-methylcephalosporins having the formula ##STR5## o. D. M. Brunwin et al., J. Chem. Soc. Chem. Comm., 865 (1971) describing synthesis of compounds of the formula ##STR6## p. S. Wolfe et al., Canadian J. Chem., 50, 2902 (1972) describing compounds of the formula ##STR7## q. J. P. Luttringer et al., Tetrahedron Letters, 4163-4166 (1973) describing compounds of the formula ##STR8## PA1 1. reacting an ester of the formula ##STR71## wherein R' is an easily cleavable ester carboxyl-protecting group with cinnamaldehyde in an inert organic solvent in the presence of a drying agent or with azeotropic removal of water to produce an imine of the formula ##STR72## wherein R' is as defined above; 2. reacting said imine of formula XII with an azidoacetyl halide or an azidoacetic mixed anhydride in the presence of an organic base to produce a cis-.beta.-lactam compound of the formula ##STR73## wherein R' is as defined above; 3. subjecting said .beta.-lactam compound of formula IV to ozonolysis to produce an aldehyde of the formula ##STR74## wherein R' is as defined above; 4. selectively reducing said aldehyde of formula XXVIII to the corresponding alcohol of the formula ##STR75## wherein R' is as defined above; 5. reacting the alcohol of formula XIII with an acid anhydride, preferably acetic anhydride or trifluoroacetic anhydride, in the presence of a Lewis acid to produce a compound of the formula ##STR76## wherein R' is as defined above and An represents the residue of the acid anhydride; PA1 6. subjecting the compound of formula XIV to acid hydrolysis to produce a compound of the formula ##STR77## wherein R' is as defined above; 7. reacting the compound of formula XV with an amine, preferably a saturated cyclic secondary amine, to produce an enamine compound of the formula ##STR78## wherein R' is as defined above and X" is the residue of the amine; 8. reacting the enamine of formula XVI with a (lower)alkylsulfonating agent in the presence of an acid acceptor to produce a derivative of the formula ##STR79## wherein R' and X" are as defined above; 9. subjecting said derivative of formula XVII to acid hydrolysis to produce an enol intermediate of the formula ##STR80## wherein R' is as defined above; 10. cyclizing said enol intermediates by treatment with base to produce an azido 0-2-isocephem intermediates of the formula ##STR81## wherein R' is as defined above; 11. selectively reducing said azido intermediate of formula Va to produce a 7-amino 0-2-isocephem intermediate of the formula ##STR82## wherein R' is as defined above; and 12. N-acylating said 7-amino intermediate of formula VIIa or a salt thereof with an acylating acid of the formula EQU R--COOH PA1 13. removing by methods known per se the carboxyl-protecting group R' to produce the corresponding free acid compound of formula II; PA1 14. converting the free acid compound of formula II to a physiologically hydrolyzed ester thereof by methods known per se; or PA1 15. converting the free acid compound of formula II or a physiologically hydrolyzed ester thereof to a pharmaceutically acceptable salt thereof by methods known per se. PA1 1. removing by methods known per se the carboxyl-protecting group R' to produce the corresponding free acid compound of formula II; PA1 2. converting the free acid compound of formula II to a physiologically hydrolyzed ester thereof by methods known per se; or PA1 3. converting the free acid compound of formula II or a physiologically hydrolyzed ester thereof to a pharmaceutically acceptable salt thereof by methods known per se. PA1 1. reacting a ketal amine of the formula ##STR102## wherein R' represents an easily cleavable ester carboxyl-protecting group and W is alkyl or aralkyl with cinnamaldehyde in an inert organic solvent in the presence of a drying agent or with azeotropic removal of water to produce an imine of the formula ##STR103## wherein R' and W are as defined above; 2. reacting said imine with an azidoacetyl halide or an azidoacetic mixed anhydride in the presence of a base to produce a cis-.beta.-lactam compound of the formula ##STR104## wherein R' and W are as defined above; 3. subjecting said 62-lactam compound of formula XXIV to ozonolysis to produce an aldehyde of the formula ##STR105## wherein R' and W are as defined above; 4. selectively reducing the aldehyde of forumula XXV to the corresponding alcohol of the formula ##STR106## wherein R' and W are as defined above; 5. reacting said alcohol with a (lower)alkylsulfonating agent in the presence of an acid acceptor to produce a derivative of the formula ##STR107## wherein R' and W are as defined above; 6. subjecting said derivative of formula XXVII to acid hydrolysis to form an enol of the forula ##STR108## wherein R' and W are as defined above; 7. cyclizing the enol of formula X by treatment with base to produce an azido 0-2-isocephem intermediate of the formula ##STR109## wherein R' and W are as defined above: 8. selectively reducing the azido 0-2-isocephem intermediate of formula VIa to produce a 7-amino 0-2-isocephem intermediate of the formula ##STR110## wherein R' and W are as defined above; and 9. N-acylating said 7-amino intermediate of formula VIIIa or a salt thereof with an acylating acid of the formula EQU R--COOH PA1 10. removing by methods known per se the carboxyl-protecting group R' to produce the corresponding free acid compound of formula III; PA1 11. converting the free acid compound of formula III to a physiologically hydrolyzed ester thereof by methods known per se; or PA1 12. converting the free acid compound of formula III or a physiologically hydrolyzed ester thereof to a pharmaceutically acceptable salt thereof by methods known per se. PA1 1. removing by methods known per se the carboxyl-protecting group R' to produce the corresponding free acid compound of formula III; PA1 2. converting the free acid compound of formula III or a physiologically hydrolyzed ester thereof by methods known per se; or PA1 3. converting the free acid compound of formula III or a physiologically hydrolyzed ester thereof to a pharmaceutically acceptable salt thereof by methods known per se. PA1 1. reacting an 0-2-isocephem compound of the formula ##STR127## wherein R represents an acyl group and R' is an easily cleavable ester carboxyl-protecting group with carbon dioxide in the presence of a base in an inert organic solvent at a temperature in the range of about 0.degree. C. to -80.degree. C. to produce an acidification the compound of the formula ##STR128## wherein R and R' are as defined above, or a pharmaceutically acceptable salt thereof and optionally performing one or more of the additional steps of PA1 2. esterifying the free carboxyl group at the 3-position of compound XXII by methods known per se to produce a compound of the formula ##STR129## wherein Z is the residue of an ester group and R and R' are as defined above, or a pharmaceutically acceptable salt thereof and, if desired, performing one or more of the additional steps of PA1 f. converting by methods known per se the 4-carboxylic acid compound of step (d) or a physiologically hydrolyzed ester thereof to a pharmaceutically acceptable salt thereof.